# CELLULAR THERMOSTABILITY AND THERMOTOLERANCE

> **NIH NIH R01** · UNIVERSITY OF WATERLOO · 1992 · $91,376

## Abstract

Hyperthermia has promise as a means of cancer therapy, at least for tumors
refractory to other means of treatment but situated such that they can be
effectively heated to 43-45oC.  Most likely it will be used in combination
with radiation or certain chemotherapeutic agents.  the molecular effects
of hyperthermia are not well understood, in particular the target (if there
is a single one) of hyperthermia and the molecular basis of thermotolerance
are not known.  These two problems are intimately related since
thermotolerance is probably due to protection or stabilization of the
target.  The specific aims of this proposal are to determine if the nucleus
and subnuclear components (i.e. nuclear matrix and nucleolus), plasma
membrane, and cytoskeleton contain proteins denaturing at the predicted
transition temperature of the critical target (46oC), and if the critical
target is stabilized in thermotolerant cells, that is if its denaturation
temperature is shifted to higher values (47.3oC).  Thermostability will be
assayed by measuring the temperature at which protein denaturation occurs
in these organelles isolated from control and thermotolerant cells and in
whole CHL V79 cells using high sensitivity differential scanning
calorimetry (DSC) and fluorescence spectroscopy.  These experiments will
give information about which cellular organelles can contain the critical
target for hyperthermia and whether this target, and thus the organelle
containing it, are more thermostable in thermotolerant cells.  Whether or
not there is an increase in the level of heat shock proteins (HSP) in any
organelle demonstrating increased thermostability will be determined.
Thus, the hypothesis that HSP's are responsible for thermotolerance by
directly stabilizing cellular proteins and structures will be tested.  The
technique of thermal gel analysis will be used to determine the molecular
weights of all proteins denaturing during hyperthermia in the isolated
organelles.  In addition, the cognate form of HSP70 (HSC73) will be added
to isolated organelles to determine if it can stabilize these structures.

The long term goal is to apply the technique of thermal analysis, that is
the measurement of cellular protein denaturation by DSC and other physical
techniques, to the problem of understanding thermal damage in mammalian
cells and tissue.  Thermal analysis has potential as a means of analyzing
and predicting the thermostability, hence sensitivity to hyperthermia, of
normal and tumor tissue.

## Key facts

- **NIH application ID:** 3179959
- **Project number:** 2R01CA040251-07
- **Recipient organization:** UNIVERSITY OF WATERLOO
- **SAM.gov UEI:** RHJRA5J1A2B5
- **Principal Investigator:** JAMES R. LEPOCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $91,376
- **Award type:** 2
- **Project period:** 1985-08-01 → 1995-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179959

## Citation

> US National Institutes of Health, RePORTER application 3179959, CELLULAR THERMOSTABILITY AND THERMOTOLERANCE (2R01CA040251-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179959. Licensed CC0.

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